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Reversing EphB2 depletion rescues cognitive functions in Alzheimer model

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Abstract

Amyloid-β oligomers may cause cognitive deficits in Alzheimer’s disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer’s disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer’s disease.

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Figure 1: Amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and cause degradation of EphB2 in the proteasome.
Figure 2: Knockdown of EphB2 reduces surface NR1 levels and Fc-ephrin-B2-dependent Fos expression.
Figure 3: Knockdown of EphB2 reduces LTP in dentate gyrus granule cells of nontransgenic mice.
Figure 4: Increasing EphB2 expression rescues synaptic plasticity in hAPP mice.
Figure 5: Increasing EphB2 expression in the dentate gyrus ameliorates learning and memory deficits in hAPP mice.

Change history

  • 16 August 2011

    In Supplementary Figure 11, the legend on the y-axis for panels a and b has been corrected to be 'Relative level' instead of 'ng/ml'.

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Acknowledgements

We thank I. Ethell for the plasmid encoding the Flag-tagged EphB2 receptor; D. J. Selkoe and D. Walsh for CHO-7PA2 cells; S. Finkbeiner for the plasmid encoding the NMDA receptor subunit NR1; J. Palop for comments; H. Solanoy, M. Thwin and X. Wang for technical support; G. Howard and S. Ordway for editorial review; J. Carroll for preparation of graphics; and M. Dela Cruz for administrative assistance. The study was supported by NIH grants AG011385, AG022074 and NS041787 to L.M., a fellowship from the McBean Family Foundation to M.C., and the National Center for Research Resources Grant RR18928-01 to the Gladstone Institutes.

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M.C. and L.M. conceptualized the study. M.C., B.H., J.H. and N.D. performed experiments, and all authors participated in designing experiments and in analysing and interpreting data. M.C., B.H. and L.M. wrote the manuscript. L.M. supervised the project.

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Correspondence to Lennart Mucke.

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Competing interests

L.M. serves on the Scientific Advisory Boards of AgeneBio, Inc., Neuropore Therapies, Inc. and Probiodrug A.G.

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The file contains Supplementary Figures 1-15 with legends, Supplementary Tables 1-2, Supplementary Methods and additional references. This file was replaced on 16 August 2011. (PDF 6074 kb)

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Cissé, M., Halabisky, B., Harris, J. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47–52 (2011). https://doi.org/10.1038/nature09635

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